The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy
The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy
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DOI：
10.1158/1078-0432.ccr-18-4159
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发表时间：
2019-10-01
影响因子：
11.5
通讯作者：
Brohl, Andrew S.
中科院分区：
文献类型：
--
作者：
Knepper, Todd C.;Montesion, Meagan;Brohl, Andrew S.
目的：默克尔细胞癌（MCC）是一种罕见的侵袭性皮肤恶性肿瘤，已证明对免疫检查点抑制剂治疗敏感。在这里，我们进行了最大的基因组学研究MCC迄今为止，以表征的分子景观和评估的临床和分子相关的免疫检查点抑制剂responsibility.Experimental设计：全面的分子分析进行了317肿瘤患者MCC，包括致癌突变，肿瘤突变负荷（TMB），突变的签名，和默克尔细胞多瘤病毒（MCPyV）的评价。对于一个子集的57例患者，进行了回顾性分析，以评估临床和分子相关的免疫检查点抑制剂反应和疾病survival.Results：基因组分析揭示了双峰分布在TMB，2个分子不同的亚组。百分之九十四（n = 110）的TMB高标本表现出紫外线（UV）突变特征。在所有TMB高水平病例中均未发现MCPyV基因组DNA序列（0/117），但在63%（110/175）的TMB低水平病例中发现了MCPyV基因组DNA序列。对于36例接受检查点抑制剂治疗的可评估患者，总体缓解率为44%，缓解与审查时的生存率相关（100% vs. 20%，P < 0.001）。TMB-高/UV驱动的肿瘤的缓解率为50%，TMB-低/MCPyV阳性肿瘤的缓解率为41%（P = 0.63）。缓解率与治疗线显著相关：一线为75%，二线为39%，三线或以上为18%（P = 0.0066）。PD-1（而不是PD-L1）表达与免疫治疗反应相关（PD-1阳性和阴性分别为77%和21%，P = 0.00598）。结论：我们提供了MCC的全面基因组概况，并证明了免疫治疗反应的临床基因组学相关性。
Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhibitor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhibitor response.Experimental Design: Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational burden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a subset of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhibitor response and disease survival.Results: Genomic analyses revealed a bimodal distribution in TMB, with 2 molecularly distinct subgroups. Ninety-four percent (n = 110) of TMB-high specimens exhibited an ultraviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), but were in 63% (110/175) of TMB-low cases. For 36 evaluable patients treated with checkpoint inhibitors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, P < 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors (P = 0.63). Response rate was significantly correlated with line of therapy: 75% in firstline, 39% in second-line, and 18% in third-line or beyond (P = 0.0066). PD-1, but not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, P = 0.00598, for PD-1 positive and negative, respectively).Conclusions: We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response.